Graf, Angew, Chem. Internat., Edit 7:172-182 (1968) describes addition of amines and carboxamides to chlorosulfonyl isocyanate to produce N-chlorosulfonylureas and acyl N-chlorosulfonylureas, respectively.
U.S. Pat. Nos. 3,634,453, 4,556,672 and 4,569,942, issued Jan. 11, 1972, Dec. 3, 1985 and Feb. 11, 1986, respectively, describe preparation of 2-oxindoles of formula (I) below.
U.S. Pat. Nos. 4,652,658 and 4,665,194, issued Mar. 24, 1987 and May 12, 1987, respectively, describe a process for making 2-oxindole-1-carboxamides by reacting a 2-oxindole with chlorosulfonyl isocyanate to produce a N-chlorosulfonyl-2-oxindole-1-carboxamide which is then hydrolyzed to a 2-oxindole-1-carboxamide.
U.S. Pat. Nos. 4,952,703 and 5,086,186, issued Aug. 28, 1990 and Feb. 2, 1992, respectively, and incorporated by reference entirely, describe a process for making 2-oxindole-1-carboxamides by reaction of 2-oxindoles with trichloroacetyl isocyanate to produce N-trichloroacetyl-2-oxindole-1-carboxamides which are then hydrolyzed to 2-oxindole-1-carboxamides. The so-called hydrolysis of the N-trichloroacetyl-2-oxindole-1-carboxamides, is said to be accomplished under acid conditions by treating with an acidic reagent, such as a mineral acid (sulfuric, hydrochloric), camphorsulfonic acid, or toluenesulfonic acid, in the presence of water or an alcohol with or without an additional solvent. Favored solvents are said to be alcohol (C1-4) solvents. The preferred acidic agent is said to be sulfuric acid in methanol. Only protic acidic reagents are specifically disclosed; only sulfuric acid is demonstrated by the working examples.
U.S. Pat. Nos. 4,952,703 and 5,086,186 further state that the disclosed process is adaptable to a one-pot process, without isolation of the intermediate N-trichloroacetyl-2-oxindole-1-carboxamide. They still further declare that the trichloroacetyl isocyanate can be used in premade form or it can be prepared in situ by reacting trichloroacetyl chloride and potassium cyanate in a reaction-inert solvent such as acetone. They specifically state, "The in situ preparation comprises reacting trichloroacetyl chloride and potassium cyanate in a reaction-inert solvent such as acetone in a molar ratio of from about 1:1 to 1:5. In practice, it is preferred to first react the trichloroacetyl chloride and potassium cyanate in acetone at about room temperature and then to add the oxindole reactant in acetone solution. The reaction is gradually heated to about 50.degree. C. up to the reflux temperature of the solvent until substantially complete as indicated by thin layer chromatography (TLC). The trichloroacetyloxindole carboxamide product can be recovered by known procedures. Alternatively, the trichloroacetyloxindole carboxamide is hydrolyzed in the same reaction vessel by addition of an acidic reagent, preferably sulfuric acid/methanol as described above." Neither the suggested one-pot process (without the recovery of N-trichloroacetyl-2-oxindole-1-carboxamide intermediate), nor the prescribed preparation of trichloroacetyl isocyanate in situ is demonstrated by the working examples.
While investigating the potential for practical use of the process described in the aforementioned U.S. Pat. Nos. 4,952,703 and 5,086,186, the present inventor discovered that the prescribed one-pot adaptation with in situ preparation of the trichloroacetyl isocyanate gives poor yields of 2-oxindole-1-carboxamide in the so-called hydrolysis step (which is actually an alcoholysis) compared to the step-wise process with isolation of the N-trichloroacetyl-2-oxindole-1-carboxamide intermediate or to the one-pot process using premade trichloroacetyl isocyanate. This result is believed to be due to the presence of acetone, the prescribed solvent for the in situ preparation of the trichloroacetyl isocyanate, when carried forward, as prescribed, into the alcoholysis step. Acetone is known to undergo various self-condensation and cross condensation reactions in the presence of acidic reagents.
The present inventor further discovered that the protic acid reagent used in the alcoholysis step gives less-than-desired selectivity towards alcoholysis at the intended terminal amide bond. The N-trichloroacetyl-2-oxindole-1-carboxamide intermediates have four amide bonds (carbonyl carbon-nitrogen bonds) which may be susceptible to alcoholysis, as indicated by the crooked "break" lines in the formula (IV). To the extent that alcoholysis occurs at the unintended amide bonds in either the N-trichloroacetyl-2-oxindole-1-carboxamide reactant or the desired 2-oxindole-1-carboxamide product, the product yield is decreased. For at least certain desired 2-oxindole-1-carboxamide products, for example 5-chloro-2-oxindole-1-carboxamide (X=5-Cl, Y=H, R=H), the protic acid reagent causes significant methanolysis of the cyclic amide bond in the oxindole structure leading to the ring-opened by-product of formula (V) which is difficult to remove from the desired product. This results in not only a decreased yield but product of lesser purity, unless additional purification measures are undertaken which may in turn result in a still lower recovered yield. ##STR1##